A recent study (Nature Med 2006;12:1365) showed that elevated circulating lipopolysaccharide (LPS), a consequence of microbial translocation from a leaky gut, is a cause of systemic immune activation in chronic HIV infection. LPS induces monocyte activation, monocyte trafficking across the blood-brain barrier (BBB), and BBB damage, which are key mechanisms implicated in the pathogenesis of HIV-associated dementia (HAD). Our preliminary studies demonstrated higher plasma LPS levels in AIDS patients compared to uninfected controls (p=0.0005). High LPS was associated with increased monocyte activation markers and LPS-binding protein (LBP) levels in plasma. LPS levels were higher in HAD subjects compared to those with no neurocognitive impairment (NCI), and were associated with HAD independently of plasma viral load and CD4 counts. LPS levels were higher in AIDS patients using IV heroin (p<0.0001), but not IV cocaine, compared to AIDS patients with no substance abuse. The goal of this proposal is to understand the role of microbial translocation from the gut and elevated circulating LPS in biological processes that lead to NCI in HIV-infected individuals with AIDS. We hypothesize that increased circulating LPS levels, a consequence of microbial translocation from a leaky gut, contributes to development of NCI by enhancing monocyte activation and trafficking, macrophage activation in brain, and BBB damage. High plasma LPS levels in heroin IVDU AIDS patients, possibly a consequence of increased susceptibility to bacterial infections, high rate of HCV coinfection, and/or decreased immune responses, may contribute to processes that lead to NCI in heroin IVDU by promoting monocyte neuroinvasion and neuroinflammation. To investigate these questions, we propose two specific aims: 1) determine whether plasma LPS and other markers of microbial translocation are predictive biomarkers that increase together with monocyte activation markers (e.g., sCD14, IL-6, and CCL2/MCP-1) in plasma and/or CSF of AIDS patients prior to development of HAD;and 2) determine the association between high plasma LPS in AIDS patients and evidence of monocyte neuroinvasion, macrophage/microglia activation in brain, and blood-brain barrier damage, and the influence of IV heroin use on these processes. The studies will analyze longitudinal and cross-sectional samples of blood and CSF, and autopsy brain tissue samples from AIDS subjects in the NNTC. These studies will provide insights into the role of microbial translocation from the gut in HIV pathogenesis and NCI in AIDS patients, and may identify specific mechanisms linked to NCI in HIV- infected IV heroin users as well as new potential therapeutic strategies for HIV/AIDS. PUBLIC HEALTH RELEVANCE: Project Narrative The goal of this project is to understand the role of bacterial products that translocate from the gut, a consequence of HIV infection in gut-associated lymphoid tissue, in processes that lead to neurocognitive impairment and neurological injury in HIV-infected individuals with AIDS. The studies will provide insights into the role of gut disease and gut microbes in mechanisms that lead to immune system dysfunction and neurological injury in people with AIDS, and the influence of intravenous heroin use on these processes. The studies will also provide information that could help to identify new potential therapeutic strategies for HIV/AIDS.